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Vol. 286, Issue 1, 234-242, July 1998
Department of Pharmacology, College of Medicine, University of
California, Irvine, Irvine, California
The ability of the M2 muscarinic receptor to inhibit
the relaxant effects of forskolin and isoproterenol was investigated in
bovine trachea. In most experiments, we measured contractile responses
to oxotremorine-M in smooth muscle isolated from bovine trachea in
which a majority of M3 receptors were inactivated by treatment with N-(2-chloroethyl)-4-piperidinyl diphenylacetate. In the
presence of histamine (20 µM), the histamine H2
antagonist cimetidine (10 µM) and forskolin (4 µM), responses to
oxotremorine-M were antagonized by
[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepine-6-one (1 µM) in a manner consistent with contractions mediated
predominantly by M2 receptors. When similar experiments
were conducted in the presence of isoproterenol (0.1 µM) instead of
forskolin, contractions were antagonized in a manner consistent with an
M3 receptor-mediated response. In similar experiments, we
measured the relaxant potency of isoproterenol and forskolin against
histamine-induced contractions in N-(2-chloroethyl)-4-piperidinyl
diphenylacetate-treated trachea. By itself, oxotremorine-M (7.5 nM) had
no contractile effect; however, it caused a substantial reduction in
the relaxant potency of forskolin although having little effect on that
of isoproterenol. These experiments establish that M2
receptors inhibit the relaxant effects of forskolin, but not
isoproterenol. In untreated tissues, the relaxant responses to
isoproterenol and forskolin were 10.8- and 14.2-fold more potent,
respectively, against histamine than against oxotremorine-M-induced
contractions of equal magnitude. Similarly, the maximal stimulation of
cAMP accumulation elicited by isoproterenol and forskolin was inhibited
58 and 62%, respectively, in the presence of oxotremorine-M (80 nM)
compared to that measured in the presence of histamine (20 µM).
Analysis of the data indicated that isoproterenol elicited relaxation
at concentrations well beyond those that stimulated maximal levels of
cAMP accumulation. Our results indicate that part of the relaxant
response to isoproterenol is mediated through a non-cAMP-dependent
mechanism, and that this mechanism is largely unopposed by the
M2 receptor.
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